Evaluation of curative anticryptosporidial activity of paromomycin in a dexamethasone-treated rat model

Abstract

A dexamethasone-treated rat model of cryptosporidiosis was used to evaluate the curative activity of paromomycin. Although eradication of the parasite could not be demonstrated, statisticall significant decreases in oocyst excretion and in the intensity of ileal parasitism were observed in animals receiving 100 mg of paromomycin per kg of body weight per day.Intestinal infection by Cryptosporidium parvum is a severe clinical complication of immunodepression, especially that by AIDS, leading to chronic debilitating diarrhea and severe malnutrition. Although a large number of drugs have been tried, none have proven appropriate (4).Several case reports and uncontrolled trials (1, 3, 8, and unpublished personal observations) have suggested that paromomycin, an orally administered aminoglycoside, has anticryptosporidial activity. Few experimental data on the anticryptosporidial effect of paromomycin are available. A reduction in oocyst production (5) and an inhibition of the development of intracellular stages (9) have been found in in vitro models. Recently, a prophylactic effect of paromomycin in the neonatal BALB/c mouse model (6) was reported.We tested the curative activity of paromomycin in an immunosuppressed rat model of cryptosporidiosis (10).Sixty female Sprague-Dawley rats weighing 200 to 215 g were given dexamethasone in drinking water at a concentration of 0.25 mg/kg of body weight per day throughout the experiment. Ten days after the beginning of immunosuppressive therapy, the animals were randomly divided into four groups of 15 animals and inoculated intragastrically with 4 x 105 oocysts of C. parvum of human origin, propagated in calves (M. Naciri, Institut National de la Recherche Agronomique, Tours, France). Ten days after oocyst challenge, the four groups of animals received 10, 50, or 100 mg of paromomycin sulfate (Parke-Davis, Courbevoie, France) per kg per day or distilled water (control group) by gavage twice daily.Fecal pellets were collected every 3 days for 12 h, and oocysts were counted by using an oocyst-specific monoclonal antibody-based direct immunofluorescence assay (Pasteur-Diagnostics, Maine-la-Coquette, France). All animals were killed after 10 days of paromomycin treatment. Two As shown in Table 1, rats treated with 100 mg of paromomycin per kg per day had significantly lower levels of oocyst excretion than those treated with 10 mg/kg/day and controls. Because a spontaneous decrease in oocyst output was observed in the control group, the comparison was based on the ratio of oocyst excretion on day 8 to oocyst excretion on day 17. Histological study of the ileum produced similar results (Table 1). The numbers of parasites were significantly lower in rats receiving 100 mg of paromomycin per kg per day, in which only mild infections occurred. Animals receiving 50 mg of paromomycin per kg per day tended to be less infected than controls and those receiving 10 mg/kg/day, and there were highly significant relationships between log doses of the drug and both oocyst shedding on day 17 an...

Evaluation of high-dose regimen of paromomycin against cryptosporidiosis in the dexamethasone-treated rat model

“…As in previous animal model studies (8,9,19,21), the minimal dosage of paromomycin associated with a significant effect (i.e., 50 mg/kg/day) was higher than the dosage range currently used for human patients (25 to 50 mg/kg/day). However, no eradication could be demonstrated when paromomycin at up to 400 mg/kg/day was used, so only a beneficial effect on symptoms rather than a clearing of the infection may be expected from increasing the dosage regimen in human patients.…”

“…Only paromomycin and, to a lesser extent, azithromycin have shown some benefit for patients. Paromomycin has been shown to have an anticryptosporidal effect in in vitro assays (7, 13), animal models (8,9,17,19,21), and uncontrolled clinical evaluations (1, 2, 5, 10, 11). In AIDS patients, the beneficial but limited effect of paromomycin at 25 to 35 mg/kg/day upon oocyst shedding and stool frequency has been demonstrated (22).…”

“…In a previous study, we found that paromomycin at 100 mg/kg/day, but not 50 mg/kg/day, was associated with a significant decrease in oocyst shedding and in the intensity of ileal infection (21). Similarly, in the hydrocortisone protein-deprived rat model, paromomycin treatment at the dosage of 50 mg/kg/day was found to be ineffective (3).…”

Concurrent Cryptosporidium and parvovirus infections in a puppy

“…Paromomycin, an aminoglycoside antibiotic, has shown most promise, with demonstrated efficacy in both in vitro studies and in vivo use in humans and experimental animals. [27][28][29] This drug has also been used in a small number of dogs 30 and cats 31 with cryptosporidiosis and was found to clear the faeces of oocysts within 5 days of treatment. However, a recent report attributing acute renal failure to intestinal absorption of paromomycin in four cats has raised doubts about the safety of this drug in individuals with severe gastrointestinal pathology.…”

Synergistic anticryptosporidial potential of the combination alpha-1-antitrypsin and paromomycin

“…Marshall and Flanigan (18) reported a significant reduction in C. parvum infection in vitro with paromomycin. Further studies have reported a significant anticryptosporidial effect for paromomycin in several in vivo models (9,15,(23)(24)(25) and in human clinical trials (4,6,10,11,14). Fayer and Ellis (8) evaluated the anticryptosporidial efficacy of selected aminoglycosides including paromomycin, in single-and combined-therapy trials with tetracycline in a neonatal mouse model.…”